Adasuve

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Adasuve

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Bronchospasm

ADASUVE can cause bronchospasm that has the potential to
lead to respiratory distress and respiratory arrest [see ADVERSE REACTIONS].
Administer ADASUVE only in an enrolled healthcare facility that has immediate
access on-site to equipment and personnel trained to manage acute bronchospasm,
including advanced airway management (intubation and mechanical ventilation) [see
BOXED WARNING].

Prior to administering ADASUVE, screen patients regarding
a current diagnosis or history of asthma, COPD, and other lung disease
associated with bronchospasm, acute respiratory symptoms or signs, current use
of medications to treat airways disease, such as asthma or COPD; and examine
patients (including chest auscultation) for respiratory abnormalities (e.g.,
wheezing) [See DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS].
Monitor patients for symptoms and signs of bronchospasm (i.e., vital signs and
chest auscultation) at least every 15 minutes for a minimum of one hour
following treatment with ADASUVE [see DOSAGE AND ADMINISTRATION].
ADASUVE can cause sedation, which can mask the symptoms of bronchospasm.

Because clinical trials in patients with asthma or COPD
demonstrated that the degree of bronchospasm, as indicated by changes in forced
expiratory volume in 1 second (FEV1), was greater following a second dose of
ADASUVE, limit ADASUVE use to a single dose within a 24 hour period.

Advise all patients of the risk of bronchospasm. Advise
them to inform the healthcare professional if they develop any breathing
problems such as wheezing, shortness of breath, chest tightness, or cough
following treatment with ADASUVE.

ADASUVE REMS to Mitigate Bronchospasm

Because of the risk of bronchospasm, ADASUVE is available
only through a restricted program under a REMS called the ADASUVE REMS. [see BOXED
WARNING] Required components of the
ADASUVE REMS are:

Healthcare facilities that dispense and administer
ADASUVE must be enrolled and comply with the REMS requirements. Certified
healthcare facilities must have on-site access to equipment and personnel
trained to provide advance airway management, including intubation and
mechanical ventilation.

Wholesalers and distributors that distribute ADASUVE must
enroll in the program and distribute only to enrolled healthcare facilities.

Further information is available at www.adasuverems.com
or 888-970-7367.

Elderly patients with dementia-related psychosis treated
with antipsychotic drugs are at increased risk of death. Analyses of 17
placebo-controlled trials (modal duration of 10 weeks), largely in patients
taking atypical antipsychotic drugs, revealed a risk of death in drug-treated
patients of 1.6 to 1.7 times the risk of death in placebo-treated patients.
Over the course of a typical 10-week controlled trial, the rate of death in
drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the
placebo group. Although the cases of death were varied, most of the deaths
appeared to be either cardiovascular (e.g., heart failure, sudden death) or
infectious (e.g., pneumonia) in nature. Observational studies suggest that,
similar to atypical antipsychotic drugs, treatment with conventional
antipsychotic drugs may increase mortality. The extent to which the findings of
increased mortality in observational studies can be attributed to the antipsychotic
drug as opposed to some characteristic(s) of the patients is not clear. ADASUVE
is not approved for the treatment of elderly patients with dementia-related
psychosis [see BOXED WARNING].

The diagnostic evaluation of patients with this syndrome
is complicated. It is important to consider the presence of other serious
medical conditions (e.g., pneumonia, systemic infection, heat stroke, primary
CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, or
drug fever).

The management of NMS should include: 1) immediate
discontinuation of antipsychotic drugs and other drugs that may contribute to
the underlying disorder, 2) intensive symptomatic treatment and medical
monitoring, and 3) treatment of any concomitant serious medical problems. There
is no general agreement about specific pharmacological treatment regimens for
NMS.

If a patient requires antipsychotic drug treatment after
recovery from NMS, the potential reintroduction of drug therapy should be
carefully considered. The patient should be carefully monitored, since
recurrences of NMS have been reported.

In the presence of severe hypotension requiring
vasopressor therapy, the preferred drugs may be norepinephrine or
phenylephrine. Epinephrine should not be used, because beta stimulation may
worsen hypotension in the setting of ADASUVE-induced partial alpha blockade.

In short-term (24-hour) placebo-controlled trials of
patients with agitation associated with schizophrenia or bipolar I disorder,
hypotension occurred in 0.4% and 0.8% in the ADASUVE 10 mg and placebo groups,
respectively. There were no cases of orthostatic hypotension, postural
symptoms, presyncope or syncope. A systolic blood pressure ≤ 90 mm Hg
with a decrease of ≥ 20 mm Hg occurred in 1.5% and 0.8% of the ADASUVE 10
mg and placebo groups, respectively. A diastolic blood pressure ≤ 50 mm
Hg with a decrease of ≥ 15 mm Hg occurred in 0.8% and 0.4% of the ADASUVE
10 mg and placebo groups, respectively.

In 5 Phase 1 studies in normal volunteers, the incidence
of hypotension was 3% and 0% in ADASUVE 10 mg and the placebo groups,
respectively. The incidence of syncope or presyncope in normal volunteers was
2.3% and 0% in the ADASUVE and placebo groups, respectively. In normal volunteers,
a systolic blood pressure ≤ 90 mm Hg with a decrease of ≥ 20 mm Hg
occurred in 5.3% and 1.1% in the ADASUVE and placebo groups, respectively. A
diastolic blood pressure ≤ 50 mm Hg with a decrease of ≥ 15 mm Hg
occurred in 7.5% and 3.3% in the ADASUVE and placebo groups, respectively.

Seizures

ADASUVE lowers the seizure threshold. Seizures have
occurred in patients treated with oral loxapine. Seizures can occur in
epileptic patients even during antiepileptic drug maintenance therapy. In short
term (24 hour), placebo-controlled trials of ADASUVE, there were no reports of
seizures.

Potential for Cognitive and Motor Impairment

ADASUVE can impair judgment, thinking, and motor skills.
In short-term, placebo-controlled trials, sedation and/or somnolence were
reported in 12% and 10% in the ADASUVE and placebo groups, respectively. No
patients discontinued treatment because of sedation or somnolence.

The potential for cognitive and motor impairment is
increased when ADASUVE is administered concurrently with other CNS depressants [see
DRUG INTERACTIONS]. Caution patients about operating hazardous
machinery, including automobiles, until they are reasonably certain that
therapy with ADASUVE does not affect them adversely.

Cerebrovascular Reactions, Including Stroke, in Elderly
Patients with Dementia-Related Psychosis

In placebo-controlled trials with atypical antipsychotics
in elderly patients with dementia-related psychosis, there was a higher
incidence of cerebrovascular adverse reactions (stroke and transient ischemic
attacks), including fatalities, compared to placebo-treated patients. ADASUVE
is not approved for the treatment of patients with dementia-related psychosis [see
BOXED WARNING].

Anticholinergic Reactions Including Exacerbation of
Glaucoma and Urinary Retention

ADASUVE has anticholinergic activity, and it has the
potential to cause anticholinergic adverse reactions including exacerbation of
glaucoma or urinary retention. The concomitant use of other anticholinergic
drugs (e.g., antiparkinson drugs) with ADASUVE could have additive effects.

Patient Counseling Information

Bronchospasm

Advise patients and caregivers that there is a risk of
bronchospasm. Advise patients to inform their healthcare professional if they
develop any breathing problems such as wheezing, shortness of breath, chest
tightness, or cough following treatment with ADASUVE [see BOXED WARNING and
WARNINGS AND PRECAUTIONS]

Interference with Cognitive and Motor Performance

Caution patients and caregivers about performing
activities requiring mental alertness, such as operating hazardous machinery or
operating a motor vehicle, until they are reasonably certain that ADASUVE has
not affected them adversely [see WARNINGS AND PRECAUTIONS].

Neuroleptic Malignant Syndrome

Patients and caregivers should be counseled that a
potentially fatal symptom complex sometimes referred to as NMS has been
reported in association with administration of antipsychotic drugs. Signs and
symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status,
and evidence of autonomic instability (irregular pulse or blood pressure,
tachycardia, diaphoresis, and cardiac dysrhythmia) [see WARNINGS AND
PRECAUTIONS].

Hypotension and Syncope

Advise patients and caregivers of the risk of hypotension
or orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon
standing) [see WARNINGS AND PRECAUTIONS].

Anticholinergic Reactions

Counsel patients and caregivers about the potential risks
of anticholinergic reactions, such as exacerbation of glaucoma and urinary
retention [see WARNINGS AND PRECAUTIONS].

Pregnancy

Counsel patients and caregivers regarding the potential
risk to the fetus or neonate [see Use in Specific Populations].

Nursing Mothers

Counsel patients and caregivers regarding the potential
risk to the infant [see Use in Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No adequate studies have been conducted.

Mutagenesis

Loxapine did not cause mutation or chromosomal aberration
when tested in vitro and in vivo. Loxapine was negative in the Ames gene
mutation assay, the human peripheral blood lymphocyte chromosomal aberration
assay, and in the in vivo mouse bone marrow micronucleus assay up to 40 mg/kg
(20-fold the MRHD on mg/m² basis).

Loxapine metabolite 8-OH-loxapine was not mutagenic in
the in vitro Ames reverse mutation assay and was not clastogenic in the in
vitro human peripheral blood lymphocyte chromosomal aberration assay.

Impairment of Fertility

Loxapine had no effects on fertility or early embryonic
development in male rats or in male and female rabbits following oral
administration. Mating was decreased in female rats because these animals were
in persistent diestrus, an expected pharmacologic effect for this class of
compounds. This occurred at doses approximately 0.2- and 1-fold the MRHD of 10
mg/day on a mg/m² basis.

Use In Specific Populations

In general, no dose adjustment for ADASUVE is required on
the basis of a patient's age, gender, race, smoking status, hepatic function,
or renal function.

Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies of
ADASUVE use in pregnant women. Neonates exposed to antipsychotic drugs during
the third trimester of pregnancy are at risk for extrapyramidal and/or
withdrawal symptoms following delivery. Loxapine, the active ingredient in
ADASUVE, has demonstrated increased embryofetal toxicity and death in rat
fetuses and offspring exposed to doses approximately 0.5-fold the maximum
recommended human dose (MRHD) on a mg/m² basis. ADASUVE should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.

Human Data

Neonates exposed to antipsychotic drugs during the third
trimester of pregnancy are at risk for extrapyramidal and/or withdrawal
symptoms following delivery. There have been reports of agitation, hypertonia,
hypotonia, tremor, somnolence, respiratory distress, and feeding disorders in
these neonates. These complications have varied in severity; in some cases
symptoms have been self-limited, but in other cases neonates have required
intensive care unit support and prolonged hospitalization.

Animal Data

In rats, embryofetal toxicity (increased fetal
resorptions, reduced weights, and hydronephrosis with hydroureter) was observed
following oral administration of loxapine during the period of organogenesis at
a dose of 1 mg/kg/day. This dose is equivalent to the MRHD of 10 mg/day on a
mg/m² basis. In addition,
fetal toxicity (increased prenatal death, decreased postnatal survival, reduced
fetal weights, delayed ossification, and/or distended renal pelvis with reduced
or absent papillae) was observed following oral administration of loxapine from
mid-pregnancy through weaning at doses of 0.6 mg/kg and higher. This dose is
approximately half the MRHD of 10 mg/day on a mg/m² basis.

No teratogenicity was observed following oral
administration of loxapine during the period of organogenesis in the rat,
rabbit, or dog at doses up to 12, 60, and 10 mg/kg, respectively. These doses
are approximately 12-, 120-, and 32-fold the MRHD of 10 mg/day on a mg/m² basis, respectively.

Nursing Mothers

It is not known whether ADASUVE is present in human milk.
Loxapine and its metabolites are present in the milk of lactating dogs. Because
many drugs are excreted in human milk and because of the potential for serious
adverse reactions in nursing infants from

ADASUVE, a decision should be made whether to discontinue
nursing or discontinue ADASUVE, taking in to account the importance of the drug
to the mother.

Pediatric Use

The safety and effectiveness of ADASUVE in pediatric
patients have not been established.

Geriatric Use

Elderly patients with dementia-related psychosis treated
with antipsychotic drugs are at an increased risk of death [see BOXED
WARNING and WARNINGS AND PRECAUTIONS]. ADASUVE is not approved for
the treatment of dementia-related psychosis. Placebo-controlled studies of
ADASUVE in patients with agitation associated with schizophrenia or bipolar
disorder did not include patients over 65 years of age.

Last reviewed on RxList: 1/14/2013
This monograph has been modified to include the generic and brand name in many instances.